Plasma lipidome mediates the causal effect of chronic hepatitis B on cirrhosis: A Mendelian randomization study

This study aimed to investigate the role of the plasma lipid species in the progression from chronic hepatitis B (CHB) infection to cirrhosis. We conducted 2-sample Mendelian randomization (MR) and genome-wide mediation analyses to explore the causal relationship between CHB and cirrhosis, focusing on lipid species as potential mediators. The inverse variance weighted method was used as the primary analytical approach, supported by complementary estimators. Sensitivity analyses - including Cochran's Q test, MR-Egger intercept test, of Mendelian randomization pleiotropy residual sum and outlier global test, and leave-one-out analysis - were performed to assess robustness, heterogeneity, and horizontal pleiotropy. We found a significant positive association between CHB and cirrhosis (odds ratio = 1.206; 95% CI: 1.080 to 1.346; P = .001). Among 179 common lipid species analyzed, genetic predispositions for 29 were significantly associated with CHB and 4 with cirrhosis. Mediation analysis identified 2 lipid species - ceramide (d40:2) and phosphatidylcholine (18:2_20:4) - as potential mediators in the causal pathway from CHB to cirrhosis. Ceramide (d40:2) mediated 11.65% of the effect (mediation effect: 0.022; 95% CI: 0.002 to 0.049; P = .037), while phosphatidylcholine (18:2_20:4) mediated 6.62% (mediation effect: 0.012; 95% CI: -0.0003 to 0.030; P = .072). Overall, this study provides genetic evidence supporting the causal role of CHB in the development of cirrhosis and highlights ceramide (d40:2) and phosphatidylcholine (18:2_20:4) as key mediators in this process.